1. Field of the Invention
This invention relates to a method of improving recovery after surgery by preventing the catabolic reaction and insulin resistance caused by surgical trauma.
2. Background Information
Approximately 20-25,000 surgical treatments per million inhabitants are performed annually in the western world. Surgery, like any trauma, initiates marked changes in metabolism [Shaw, J. H. F., et al., Ann. Surg., 209(1):63-72 (1989); Little, R. A., et al., Prog. Clin. Biol. Res. 263A:463-475 (1987); Frayn, K. N., Clin. Endocrinol. 24:577-599 (1986); Brandi, L., et al., Clin. Sci. 85:525-35 (1993)]. Accelerated synthesis of glucose, the primary fuel of tissue repair, is an important metabolic change after surgery, and occurs at the expense of body protein and energy stores [Gump, F. E., et al., J. Trauma, 14:378-88 (1974); Black, R. B., et al., Ann. Surg. 196:420-35 (1982)].
These changes have previously been attributed to the gluco-regulatory stress hormones and other catabolic factors, such as cytokines, that are released as a response to trauma. The more marked the change toward catabolism, the greater is the morbidity, and the slower is the recovery of the patient [Thorell, A., et al., Eur. J. Surg., 159:593-99 (1993); Chernow, B., et al., Arch. Intern. Med., 147:1273-8 (1987)].
Post-operative catabolic states may be treated with anabolic hormones, particularly, Growth Hormone and IGF-1 [Hammarkvist, F., et al., Ann. Surg., 216(2):184-190 (1991); Ziegler, T., et al., Annu. Rev. Med., 45:459-80 (1994); Ziegler, T. R., et al. J. Parent. Ent. Nutr. 14(6):574-81 (1990)]. Some studies show a clear benefit from insulin treatment in catabolic trauma patients [Hinton, P., et al., Lancet, 17(April):767-69 (1971); Shizgal, H., et al., Am. J. Clin. Nutr., 50:1355-63 (1989); Woolfson, A. M. J., et al., N. Clin. Nutr., 50:1355-63 (1989); Woolfson, A. M. J., et al., N. Engl. J. Med. 300:14-17 (1979); Brooks, D., et al., J. Surg. Res. 40:395-405 (1986); Sakurai; Y., et al., Ann. Surg. 222:283-97 (1995)].
Yet other studies, however, show that the post-operative benefits of insulin are often compromised by insulin resistance. In insulin resistance, normal concentrations of insulin elicit less than normal responses. Insulin resistance may be due to a decrease in binding of insulin to cell-surface receptors, or to alterations in intracellular metabolism. The first type, characterized as a decrease in insulin sensitivity, can typically be overcome by increased insulin concentration. The second type, characterized as a decrease in insulin responsiveness, cannot be overcome by large quantities of insulin.
Insulin resistance following trauma can be overcome by doses of insulin that are proportional to the degree of insulin resistance, and thus is apparently a decrease in insulin sensitivity [Brandi, L. S., et al., Clin. Science 79:443-450 (1990); Henderson, A. A., et al., Clin. Sci. 80:25-32 (1990)]. Reduction in insulin sensitivity following elective abdominal surgery lasts at least five days, but not more than three weeks, and is most profound on the first post-operative day, and may take up to three weeks to normalize [Thorell, A., et al., (1993)].
The causes of the observed transient insulin resistance following trauma are not well-understood. Both cortisol and glucagon may contribute to the catabolic response to trauma [Alberti, K. G. M. M., et al., J. Parent. Ent. Nutr. 4(2): 141-46 (1980); Gelfand, R. A., et al., J. Clin. Invest. 74(December):2238-2248 (1984); Marliss, E. B., et al., J. Clin. Invest. 49:2256-70 (1970)]. However, studies of post-operative insulin resistance has failed to show any correlation between changes in these catabolic hormones and changes in insulin sensitivity after surgery [Thorell, A., et al. (1993); Thorell A., Karolinska Hospital and Institute, 104 01 Stockholm, Sweden (1993); Thorell, A, et al., Br. J. Surg. 81:59-63 (1994)].
Increased availability of lipids after trauma may induce insulin resistance through the glucose-fatty acid cycle [Randle, P. J., et al., Diab. Metab. Rev. 4(7):623-38 (1988)].
Increased availability of free fatty acids (FFA) induced insulin resistance and changed substrate oxidation from glucose to fat, even in the presence of simultaneous infusions of insulin [Ferrannini, E., et al., J. Clin. Invest. 72:1737-47 (1983); Bevilacqua, S., et al., Metabolism 36:502-6 (1987); Bevilacqua, S., et al., Diabetes 39:383-89 (1990); Bonadonna, R. C., et al., Am. J. Physiol. 259:E736-50 (1990); Bonadonna, R. C., et al., Am. J. Physiol. 257:E49-56 (1989)].
Elective surgery is routinely performed after an 15 overnight fast to reduce risks of anesthesia. This entrenched practice of fasting the patient overnight (10-16 hours) before surgery enhances the development of the catabolic state, and worsens insulin resistance. Studies in rats undergoing stress, such as hemorrhage and endotoxemia, show that fasting for periods less than 24 hours markedly affects the catabolic response to trauma [Alibegovic, A., et al., Circ. Shock, 39:1-6 (1993); Eshali, A. H., et al. Eur. J. Surg., 157:85-89 (1991); Ljungqvist, O., et al., Am. J. Physiol., 22:E692-98 (1990)]. Even a short period of fasting before the onset of a trauma in rats markedly decreases carbohydrate reserves, profoundly changes the hormonal environment, increases stress response, and, most importantly, increases mortality [Alibegovic, A., et al., Circ. Shock, 39:1-6 (1993)].
Glucose administration before surgery, either orally [Nygren, J., et al., Ann. Surg. 222:728-34 (1995)], or by infusion, reduces insulin resistance after surgery, compared to fasted patients. Patients who received overnight glucose infusions (5 mg/kg/min) before elective abdominal surgery lost an average of 32% of insulin sensitivity after the operation, while patients, entering surgery after a routine overnight fast, lost an average of 55% of their insulin sensitivity [Ljungqvist, O., et al., J. Am. Coll. Surg. 178:329-36 (1994)].
In addition to the adverse effects of fasting on recovery from surgery, immobilization of the patient and hypocaloric nutrition during and after surgery also increase insulin resistance after surgery. In healthy subjects, 24 hours of immobilization and hypocaloric nutrition have been shown to induce a 20-30% increase in peripheral insulin resistance in healthy volunteers. Thus, postoperative insulin resistance previously reported after pre-operative glucose infusions [Ljungqvist, O., (1994)] may in part be due to the additive effects of post-operative bed rest and hypocaloric nutrition.
Given the prevalence of surgery, it is important to minimize negative side-effects, such as catabolic response and insulin resistance, in order to improve healing and to reduce mortality. Post-operative insulin resistance frustrates treatment of the catabolic state with insulin. The entrenched medical practice of pre-operative fasting exacerbates post-operative catabolic state and insulin resistance. Thus, a treatment that overcomes both the catabolic state and insulin resistance is needed.
As disclosed herein, one such treatment that overcomes both the catabolic state and insulin resistance is administration of glucose and insulin together before, during, and after the operation. Insulin infusion, however, creates the potential for hypoglycemia, which is defined as blood glucose below 0.3 mM. Hypoglycemia increases the risk of ventricular arrhythmia and is a dangerous consequence of insulin infusion. An algorithm for insulin infusion for diabetics was developed to prevent hypoglycemia [Hendra, T. J., et al., Diabetes Res. Clin. Pract., 16:213-220 (1992)]. However, 21% of the patients developed hypoglycemia under this algorithm. In another study of glucose control following myocardial infarction, 18% of the patients developed hypoglycemia when infused with insulin and glucose [Malmberg, K. A., et al., Diabetes Care, 17:1007-1014 (1994)].
Insulin infusion also requires frequent monitoring of blood glucose levels so that the onset of hypoglycemia can be detected and remedied as soon as possible. In patients receiving insulin infusion in the cited study [Malmberg, 1994], blood glucose was measured at least every second hour, and the rate of infusion adjusted accordingly. Thus, the safety and efficacy of insulin-glucose infusion therapy for myocardial infarct patients depends on easy and rapid access to blood glucose data. Such an intense need for monitoring blood glucose places a heavy burden on health care professionals, and increases the inconvenience and cost of treatment. As a result, pre-surgical clinical care units often do not allot resources for monitoring and optimizing blood glucose levels before surgery, such as might be obtained by intravenous administration of insulin. Considering the risks and burdens inherent in insulin infusion, an alternate approach to pre/post-surgery control of catabolic reaction to trauma is needed.
The incretin hormone, glucagon-like peptide 1, abbreviated as GLP-1, is processed from proglucagon in the gut and enhances nutrient-induced insulin release [Krcymann B., et al., Lancet 2:1300-1303 (1987)]. Various truncated forms of GLP-1, are known to stimulate insulin secretion (insulinotropic action) and cAMP formation [see, e g., Mojsov, S., Int. J. Peptide Protein Research, 40:333-343 (1992)]. A relationship between various in vitro laboratory experiments and mammalian, especially human, insulinotropic responses to exogenous administration of GLP-1, GLP-1(7-36) amide, and GLP-1(7-37) acid has been established [see, e.g., Nauck, M. A., et al., Diabetologia, 36:741-744 (1993); Gutniak, M., et al., New England J. of Medicine, 326(20):1316-1322 (1992); Nauck, M. A., et al., J. Clin. Invest., 91:301-307 (1993); and Thorens, B., et al., Diabetes, 42:1219-1225 (1993)]. GLP-1(7-36) amide exerts a pronounced antidiabetogenic effect in insulin-dependent diabetics by stimulating insulin sensitivity and by enhancing glucose-induced insulin release at physiological concentrations [Gutniak M., et al., New England J. Med. 326:1316-1322 (1992)]. When administered to non-insulin dependent diabetics, GLP-1(7-36) amide stimulates insulin release, lowers glucagon secretion, inhibits gastric emptying and enhances glucose utilization [Nauck, 1993; Gutniak, 1992; Nauck, 1993].
The use of GLP-1 type molecules for prolonged therapy has been obstructed because the serum half-life of such peptides is quite short. For example, GLP-1(7-37) has a serum half-life of only 3 to 5 minutes. GLP-1(7-36) amide has a half-life of about 50 minutes when administered subcutaneously. Thus, these GLP molecules must be administered as a continuous infusion to achieve a prolonged effect [Gutniak M., et al., Diabetes Care 17:1039-1044 (1994)]. In the present invention, GLP-1's short half-life and the consequent need for continuous administration are not disadvantages because the patient is typically hospitalized, before surgery, and fluids are continuously administered parenterally before, during, and after surgery.